Chemotherapy in first trimester of pregnancy may highten risk of congenital anomalies: JAMA
Because chemotherapy attacks rapidly proliferating cells and is minimally selective, it also puts a developing fetus at risk of teratogenic effects. Toxic events during the periconceptional period might affect early embryogenesis and result in a miscarriage, whereas subsequent toxic exposure might interfere with the formation of organs, with the most susceptible period occurring between 2 and 8 weeks after conception (between 4 and 10 weeks postmenstruation). There is a wide consensus that chemotherapy should be administered until after organogenesis is completed, usually considered the first trimester of pregnancy (ie, the first 13 weeks postmenstruation).
However, the exact timing of conception might be uncertain, and some systems (eg, eyes, genitals, hematopoietic system, central nervous system) continue to develop after 10 weeks of gestation. Therefore, the question remains in clinical practice: at what exact gestational age can chemotherapy be safely initiated to avoid inducing congenital malformations?
To assess the immediate teratogenic role of prenatal chemotherapy, a cohort study carried out by Gerwen et al evaluated the presence of major and minor congenital malformations detected during pregnancy or at birth among the offspring of patients registered in the International Network of Cancer, Infertility and Pregnancy (INCIP).
The registry was started in 2005, and this cohort study was performed with a data cutoff of December 1, 2019. Patient data, including gestational age at treatment initiation, duration of chemotherapy during pregnancy, and obstetric and neonatal outcomes, were collected for all pregnant women who received chemotherapy with known obstetric outcomes. Congenital malformations were defined as structural or chromosomal malformations that were diagnosed prenatally or at birth.
In total, 755 pregnant women treated with chemotherapy between 1977 and 2019 were included in analysis. Breast cancer was the most common cancer type (59.8%), and most pregnancies ended in a live birth (99.4%). A total of 27 neonates (3.6%) were reported to have major congenital malformations, and 14 neonates (1.9%) had minor congenital malformations.
The occurrence of major congenital malformations was the highest if first chemotherapy exposure was prior to 12 weeks gestational age, at 21.7%, compared with 3.0% congenital malformations among offspring of women who began chemotherapy after 12 weeks gestation, with the greatest risk for women who began chemotherapy periconceptionally.
The occurrence of major malformations when chemotherapy was initiated after 12 weeks of gestation was lower and remained stable with advanced pregnancy. The occurrence of minor malformations was comparable with the rates expected in the general population when exposure occurred prior or after 12 weeks gestational age.
A total of 29 women initiated chemotherapy prior to 12 weeks of gestation. In 17 women (58.6%), pregnancy status was not known at the moment of chemotherapy initiation. A total of 6 patients (20.7%, all with hematological malignant neoplasms) experienced an early miscarriage after chemotherapy (3 women [10.3%]) or opted to terminate the pregnancy for oncological reasons (3 women [10.3%]). Of the remaining 23 neonates prenatally exposed to chemotherapy prior to 12 weeks of gestation, 6 (26.1%) had congenital malformations.
The study found an association between chemotherapy before 12 weeks of gestation and increased risk of congenital malformations detected during pregnancy or at birth. The overall congenital malformation rate among offspring of mothers who initiated chemotherapy after 12 weeks of gestation was 4.8%, which is comparable to the expected rates in the general population (ie, 2.5%-6.9% for major malformations and 6.5%-35.8% for minor malformations).
First-trimester chemotherapy exposure has been associated with 10% to 20% risk of major malformations. Mechanisms by which chemotherapeutics induce teratogenic effects are incompletely understood. To date, the reported malformations after oncological treatment during human pregnancy encompass all organ systems, without discernible pattern for most cytotoxic drugs, except for aminopterin and methotrexate. The nature of teratogenesis is extremely complex; individual genetic susceptibility, specific timing of cytotoxic exposure, and specific type of (co-)medication all determine the spectrum of anomalies.
Data on the risks of congenital malformations are indispensable for clinicians and patients when considering chemotherapy during pregnancy. Based on these findings, the authors suggest that when cancer is diagnosed in early pregnancy, chemotherapy can be initiated from 12 weeks onward.
Therefore, accurate ultrasonographic dating is crucial. The introduction of a 1-week safety period could be considered to further minimize the risk of chemotherapy-induced congenital malformations. However, no rationale exists to delay the start of chemotherapy beyond 14 weeks of gestation, as recommended previously. If a patient desires certainty on risk of chromosomal anomalies, an amniocentesis for karyotyping and microarray could be offered, since noninvasive prenatal testing is not conclusive in patients with cancer owing to tumor cell-free DNA interference.
These findings suggest that chemotherapy during the first 12 weeks of pregnancy was associated with increased risk for congenital malformations in the fetus. If an aggressive cancer diagnosis during early pregnancy does not allow treatment delay, parents should be counseled on fetal risks of malformations. If a patient incidentally becomes pregnant while receiving chemotherapy, prenatal counselling should include the risks of both short- and long-term adverse outcomes. Adequate anticonception and routine pregnancy tests should be offered to fertile women with cancer.
Source: Gerwen et al; JAMA Network Open. 2021;4(6):e2113180.
doi:10.1001/jamanetworkopen.2021.13180
